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Fig. 7.13 Structures of diltiazem and a benzozapepinone analogue resistant to metabolism.
The predominant interaction of CYP3A4 is via hydrophobic forces and the overall lowering of lipophilicity can reduce metabolic lability to the enzyme. Figure 7.14 shows the relationship between unbound intrinsic clearance in man and lipophilici-ty for a variety of CYP3A4 substrates. The substrates are cleared by a variety of metabolic routes including N-dealkylation, aromatization and aromatic and aliphatic hy-droxylation. The trend for lower metabolic lability with lower lipophilicity is maintained regardless of structure or metabolic route.
7.3 Oxidative Metabolism and Drug Design 85
Fig. 7.14 Unbound intrinsic clearance of CYP3A4 substrates and relationship with lipophilicity. The data has been calculated from various clinical studies with the drugs listed in order of decreasing lipophilicity.
Oxidative Metabolism and Drug Design
In addition to the examples indicated above the design of orally-active cholesterol absorption inhibitors combines both the concept of preventing metabolism and the serendipity of metabolites being more active than the parent drug . On the basis of metabolite structure-activity relationships for SCH 48461 (Figure 7.15), SCH 58335 was designed to combine activity-enhancing oxidation and to remove or block sites of detrimental metabolic oxidation. The improvement in the pharmacodynamics of the compound is illustrated by the ED50 being reduced in the cholesterol hamster model from 2.2 to 0.04 mg kg-1 day-1.
Fig. 7.15 Structures of cholesterol absorption inhibitors SCH 48461 (A) and SCH 58235 (B). Metabolism of SCH 48461 occurs by aromatic hydrox-ylation (1) benzylic hydroxylation (2) and O-demethylation (3, 4). Metabolism is blocked in SCH 58235 at 1 and 4 or results in increases in potency at 2 and 3.
86 7 Metabolic (Hepatic) Clearance
Fig. 7.16 Steps in the discovery of cromakalim: initial structure (A), more potent pyrrolidine analogue (B) and active metabolite (cromakalim C).
The discovery of the potassium channel opener cromakalim is another example of metabolism providing novel active molecules . The programme was designed to find agents that were antihypertensive without having р-adrenoceptor blocking activity. This was due to the belief that р-adrenoceptor blockade was not solely responsible for the antihypertensive effects of р-adrenoceptor blockers. Early compounds were synthesized as cyclized derivatives of р-adrenoceptor blockers. The initial lead is illustrated in Figure 7.16. The gem-dimethyl group and an electron-withdrawing group on the aromatic ring were essential. Cyclic amino groups were preferred to the original isopropylamine, leading to the pyrrolidine derivative. The eventual candidate cromakalim was produced by investigating the metabolites of the pyrrolidine derivative, an oxidation to amines to produce amides being a common metabolic step in cyclic amide systems.
Function of Esterases
Non-specific esterases are distributed widely throughout the body. The activity of these enzymes varies markedly within different tissues. In mammals the highest levels are found in liver and kidney. Numerous isoenzymes exist which have broad substrate overlap. A loose categorization divides the two enzyme types likely to be involved in drug hydrolysis into arylesterases and aliesterases. Aliesterases have a wide substrate range, arylesterases require a phenolic ester. Since most of the major tissues contain a mixture this division is not of great importance. Where esters are of great benefit to drug design is in the design of rapidly cleared molecules, either to an inactive or active form. The most rapid clearance is by blood metabolism. An important point in the screening of compounds designed for rapid metabolism is that the erythrocyte surface has a high esterase content and whole blood is therefore the medium of choice. Moreover rodent blood has very high esterase levels, and may
7.4 Non-Specific Esterases 87
Fig. 7.17 Proposed mechanism for non-specific esterase catalysis involving a serine residue.
give a misleading view of stability if this species is used in isolation. It is highly likely that many of these enzymes are serine esterases and a suggested mechanism is proposed in Figure 7.17.
Ester functions present in molecules tend to be considered labile although steric effects etc. may be utilized to produce drugs without inherent chemical or metabolic problems due to ester lability. For instance a series of antimuscarinic compounds which had selectivity for the M3 receptor (Figure 7.18) were stabilized by the incorporation of a hydroxyethyl side chain or a cyclic ring system at positions surrounding the ester function. Presumably the proximity of these groups to the ester function (carbonyl) prevents close approach of the “attacking” nucleophile, in this case probably a serine hydroxyl.